Fight Aging!

If you are familiar with research into those parts of lipid metabolism presently considered relevant to the development of atherosclerosis, near entirely focused on the mechanisms by which cholesterol is transported around the body in the bloodstream, then you will know that the CETP protein is considered a target for therapies. This is due to (a) its role in transferring cholesterol between transport particles such as high density lipoprotein (HDL) and low-density lipoprotein (LDL), and (b) suggestive data for gene variants to affect risk of cardiovascular disease.

LDL particles carry cholesterol outwards from the liver into the arteries where atherosclerotic plaques form. HDL particles carry cholesterol back to the liver from the rest of the body. Present therapies aimed at reducing the amount of LDL-cholesterol, such as statins and PCSK9 inhibitors, have their origins in the discovery of human mutants with lower LDL-cholesterol and lower lifetime cardiovascular risk. In practice, the resulting drugs produce only modest benefits, failing to reverse atherosclerosis even when greatly reducing LDL-cholesterol, and only reducing risk of heart attack and stroke by at most 20%, if we are being generous in our interpretation of the data. Similarly, attempts to enhance HDL transport to drain cholesterol from arteries have met with failure.

Today's open access paper is an interesting look at one slice of all of this biochemistry, focused on CETP and whether or not it is a target worth pursuing. The development of many ways to achieve small gains derived from evidence for influence of one gene or another on cholesterol transport has perhaps made some people a little hesitant to jump on yet another similar gene and similar attempt. Yet one can line up a bunch of evidence to suggest that targeting CETP will achieve some benefits, not just for cardiovascular disease, and funding has been found for clinical trials of CETP-targeted therapies.

Cholesteryl ester transfer protein inhibition: a pathway to reducing risk of morbidity and promoting longevity

Cholesteryl ester transfer protein (CETP) is a hydrophobic glycoprotein that is a member of the lipid transfer protein family. It facilitates the bidirectional exchange of cholesteryl esters and triglycerides among lipoprotein particles leading to a net mass transfer of cholesteryl esters from high-density lipoprotein (HDL) to low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) particles. In addition, triglycerides are transferred in the opposite direction from LDL and VLDL to HDL.

Interest in CETP inhibition as a therapeutic target began with the discovery in observational studies that some CETP gene polymorphisms were associated with reduced coronary heart disease (CHD) incidence and CHD mortality, although these results have not been entirely consistent. However, taking all evidence into consideration, observational studies, Mendelian randomization (MR) analyses, and randomized clinical trials of pharmaceutical agents indicate that CETP inhibition confers cardiovascular benefit and reduces risk of atherosclerotic cardiovascular disease (ASCVD). Additionally, emerging evidence suggests that CETP inhibition may promote longevity, presumably by lowering the risk of several conditions associated with aging such as new-onset type 2 diabetes mellitus (T2D), dementia, chronic kidney disease (CKD), and age-related macular degeneration (AMD), as well as promoting survival in septicemia. Some of these effects are likely mediated through improved functionality of the HDL particle, including its role on cholesterol efflux and antioxidative, anti-inflammatory, and antimicrobial activities.

At present, there is robust clinical evidence to support the benefits of reducing CETP activity for ASCVD risk reduction, and plausibility exists for the promotion of longevity by reducing risks of several other conditions. An ongoing large clinical trial program of the latest potent CETP inhibitor, obicetrapib, is expected to provide further insight into CETP inhibition as a therapeutic target for these various conditions.

Senescent cells accumulate with age and cause harm via their inflammatory signaling, contributing to the chronic inflammation of aging that is disruptive to tissue structure and function throughout the body. One faction of the research and development community wants to selectively destroy senescent cells via the use of a wide variety of senolytic therapies presently under development. Another faction wants to instead find ways to suppress the inflammatory signaling of these cells. Here find an example of this second area of research, a search for targets that can be manipulated to reduce harmful signaling generated by senescent cells, but which will produce minimal side-effects in non-senescent cells.

In this review, we summarize the current research progress on non-histone high mobility group proteins (HMGs) in the field of aging, particularly their structural characteristics and functional roles in regulating the aging process. As chromatin architectural regulators, HMGs, in collaboration with histones, exert critical influence on chromatin dynamics and gene expression. By competitively binding to specific DNA sites, HMGs alter chromatin accessibility and regulate gene activity, thereby exerting profound effects at various stages of cellular senescence. This regulation involves a wide array of mechanisms and pathways, with a particularly notable impact on the senescence-associated secretory phenotype (SASP) and senescence-associated heterochromatin foci (SAHF).

HMG proteins, particularly members of the HMGA and HMGB families, play pivotal roles in the formation and regulation of SASP and SAHF. SASP comprises pro-inflammatory factors and proteins secreted during cellular senescence, which not only drive the aging process but are also closely associated with various age-related diseases, including chronic inflammation, cardiovascular diseases, and cancer. HMGA proteins promote or inhibit the spread of inflammatory signals by affecting chromatin structure and regulating the expression of SASP-related genes. Meanwhile, HMGB proteins, acting as damage-associated molecular patterns (DAMPs), activate inflammatory pathways and exacerbate the release of SASP. SAHF, as highly compacted heterochromatin regions, silence genes related to proliferation and the cell cycle, marking cells' entry into a state of permanent cell cycle arrest. The dynamic regulation of HMG proteins is crucial for the formation and maintenance of SAHF.

Recent studies have shown that targeting and blocking HMG proteins, particularly HMGB1 and HMGA2, not only reduces the release of SASP but also effectively inhibits inflammatory responses, thereby slowing the progression of age-related diseases. By inhibiting the extracellular release of HMGB1, researchers have found that sterile inflammation and tissue damage can be alleviated, protecting cardiovascular health and delaying the development of age-related cardiovascular diseases. Targeting these proteins has become a key direction in aging research. Compared to traditional therapies, targeting HMG proteins offers a more precise means of modulating age-related pathophysiological processes with fewer effects on normal cells.

Link: https://doi.org/10.3389/fragi.2024.1486281

Generally speaking, one should expect greater disability and disease in later life to correlate with greater mortality. Yet in many mammalian species, including our own, males die younger and females exhibit greater frailty while living longer. Biology is complicated! Here, researchers single out for attention the age-related dysfunction of the immune system that leads to a growing state of unresolved, constant inflammatory signaling. This state of inflammaging is thought to differ in women versus men, and may be one of the more important contributions to the observed sex-specific differences in outcomes.

Aging is a dynamic process that requires a continuous response and adaptation to internal and external stimuli over the life course. This eventually results in people aging differently and women aging differently than men. The "gender paradox" describes how women experience greater longevity than men, although linked with higher rates of disability and poor health status. Recently, the concept of frailty has been incorporated into this paradox giving rise to the "sex-frailty paradox" which describes how women are frailer because they manifest worse health status but, at the same time, appear less susceptible to death than men of the same age. However, very little is known about the biological roots of this sex-related difference in frailty.

Inflamm-aging, the chronic low-grade inflammatory state associated with age, plays a key pathophysiological role in several age-related diseases/conditions, including Alzheimer's disease (AD), for which women have a higher lifetime risk than men. Interestingly, inflamm-aging develops at a different rate in women compared to men, with features that could play a critical role in the development of AD in women. According to this view, a continuum between aging and age-related diseases that probably lacks clear boundaries can be envisioned in which several shared biological mechanisms that progress at different pace may lead to different aging trajectories in women than in men.

Link: https://doi.org/10.1016/j.exger.2024.112619

Cellular biochemistry changes in characteristic ways with age. Aging is a stochastic process of damage accumulation, followed by diverse consequences, but there are considerable similarities under the hood for all that the final dysfunctions are so varied and individual. An intricate iron structure left unprotected in the rain will collapse in any one of a hundred different ways, but underlying all of those possible breakages is the one common process of rust. Thus any sufficiently large body of data derived from individuals of various ages, whether omics or clinical chemistry or functional tests, can be used to produce algorithm combinations of values that reflect biological age. These algorithms are known as aging clocks.

The first, and still most widely used clocks are based on epigenetic data. Specifically they make use of the methylation status of CpG sites on the genome, decorations to nuclear DNA that change its structure to expose or hide specific regions, and thus change patterns of gene expression - which proteins are produced, and in what amount. A cell is in constant feedback with itself and its environment, DNA methylation constantly changing. But some of those changes are characteristic of damage and damaged environment of aged tissues.

The challenge with DNA methylation clocks, or any other aging clock, lies in understanding how the measurements made connect to underlying processes of aging and age-related diseases. Since the clocks are produced by machine learning approaches operating on data, that understanding doesn't exist yet. It is hard to take a clock measurement at face value without either knowing how its data relates to mechanisms of aging, or without a great deal of validation using real world data. It seems plausible that the real world validation approach will beat out the slow path to sufficient understanding, at least when it comes to justifying the use of some forms of aging clock for some forms of intervention in the matter of aging.

As today's open access paper notes, DNA methylation clocks have been used in a fair number of clinical trials for interventions that might be expected to modestly adjust the pace of aging or state of aging. There is enough data to start talking about when and how we should trust these DNA methylation clock measures. Nonetheless, this is still only the first step along a much longer road. In a world in which people continue to debate the conclusions of extensive clinical data for common therapies decades after their introduction - consider aspirin use for example - rapid consensus should not be the expected outcome for any tool or treatments.

DNAm aging biomarkers are responsive: Insights from 51 longevity interventional studies in humans

Aging biomarkers can potentially allow researchers to rapidly monitor the impact of an aging intervention, without the need for decade-spanning trials, by acting as surrogate endpoints. Prior to testing whether aging biomarkers may be useful as surrogate endpoints, it is first necessary to determine whether they are responsive to interventions that target aging. Epigenetic clocks are aging biomarkers based on DNA methylation (DNAm) with prognostic value for many aging outcomes. Many individual studies are beginning to explore whether epigenetic clocks are responsive to interventions. However, the diversity of both interventions and epigenetic clocks in different studies make them difficult to compare systematically.

Here, we curate TranslAGE-Response, a harmonized database of 51 public and private longitudinal interventional studies and calculate a consistent set of 16 prominent epigenetic clocks for each study, along with 95 other DNAm biomarkers that help explain changes in each clock. With this database, we discover patterns of responsiveness across a variety of interventions and DNAm biomarkers. For example, clocks trained to predict mortality or pace of aging have the strongest response across all interventions and show consistent agreement with each other, pharmacological and lifestyle interventions drive the strongest response from DNAm biomarkers, and study population and study duration are key factors in driving responsiveness of DNAm biomarkers in an intervention. Some classes of interventions such as TNF-alpha inhibitors have strong, consistent effects across multiple studies, while others such as senolytic drugs have inconsistent effects. Clocks with multiple sub-scores (i.e. "explainable clocks") provide specificity and greater mechanistic insight into responsiveness of interventions than single-score clocks.

Our work can help the geroscience field design future clinical trials, by guiding the choice of interventions, specific subsets of epigenetic clocks to minimize multiple testing, study duration, study population, and sample size, with the eventual aim of determining whether epigenetic clocks can be used as surrogate endpoints.

The brain has evolved to operate at the edge of its capacity; the normal operation of neural tissue requires a lot of energy, derived from nutrients and oxygen provided in the blood stream. That the increased blood flow that occurs following exercise improves cognitive function in the short term is indicative that there is room for improvement in the physiological support provided by the body for the normal operation of the brain. This remains true in later life, as the data here shows.

The research team leveraged smartphone technology to interact with participants multiple times during their regular daily lives. Over the course of nine days, participants checked in six times a day, approximately every 3.5 hours. During each check-in, participants reported if they had been physically active since their last check-in. If they were active, they were asked to rate the intensity of their activity - light, moderate or vigorous. For example, walking and cleaning were considered light intensity while running, fast biking, and effortful hiking were considered vigorous intensity. Participants were then prompted to play two "brain games," one designed to assess cognitive processing speed and the other designed to assess working memory, which can be a proxy for executive function.

The team analyzed data from 204 participants who were recruited for the Multicultural Healthy Diet Study to Reduce Cognitive Decline & Alzheimer's Risk. Data was collected during the study's baseline period. Participants were between the ages of 40 and 65 and residents of the Bronx, NY who had no history of cognitive impairment. The team found that when participants reported being physically active sometime in the previous 3.5 hours, they showed improvements in processing speed equivalent to being four years younger. While there were no observed improvements in working memory, the response time during the working memory task mirrored the improvements observed for processing speed.

Additionally, people who reported being active more often experienced greater short-term benefits compared to those who reported less physical activity overall. This suggests that cognitive health benefits may increase with regular physical activity. However, more research is needed to understand how much physical activity and the frequency and timing of being active influences cognitive health.

Link: https://www.psu.edu/news/research/story/can-everyday-physical-activity-improve-cognitive-health-middle-age

Cancers evolve to co-opt aspects of the immune system in order to suppress the immune response to cancerous cells. All tumor tissues make use of a variety of such mechanisms. In principle, sabotaging the immune suppression produced by tumor tissue should be a basis for both novel effective cancer therapies and enhancement of existing immunotherapies for cancer. Here is an example of early stage research in this part of the field, in which researchers identify mechanisms operating in regulatory T cells in tumor tissue. The metabolism of tumor resident regulatory T cells may be sufficiently distinctive to build approaches to treatment that can inhibit regulatory T cell function to harm the tumor without also harming necessary immune function elsewhere in the body.

T cells are central to the body's defense against cancer, with one subset, regulatory T cells (Tregs), playing a unique and often contradictory role in immune response. Unlike conventional T cells that attack tumors, Tregs prevent excessive inflammation and maintain immune tolerance. While this is essential for immune balance, Tregs within tumors, known as tumor-infiltrating Tregs (TIL-Tregs), allow cancer to evade immune attacks by suppressing the activity of effector T cells - the immune cells that actively target and kill tumor cells. Although targeting Tregs to restore anti-tumor immunity is an emerging area in cancer therapy, systemically inhibiting Tregs can cause severe autoimmune reactions.

TIL-Tregs possess unique characteristics compared to Tregs in systemic circulation, maintaining heightened suppressive capabilities within the nutrient-poor conditions of the tumor microenvironment, where effector T cells often falter. While GLUT1 is the primary glucose transporter in conventional T cells, GLUT3 plays a central role in glucose metabolism in TIL-Tregs. Typically associated with neurons, GLUT3 enables TIL-Tregs to efficiently absorb glucose from the tumor microenvironemnt, supporting their suppressive activity.

GLUT3-driven glucose absorption activates a metabolic pathway leading to protein modification with uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a sugar molecule. This modification process, called O-GlcNAcylation, regulates various proteins, including the transcription factor c-Rel, which is essential for TIL-Tregs' tumor-specific properties. By facilitating O-GlcNAcylation, GLUT3 provides TIL-Tregs with a metabolic advantage that enhances immune suppression within tumors.

This research highlights that TIL-Tregs have unique metabolic adaptations. This paves the way for innovative strategies in cancer immunotherapy that focus on rebalancing immune responses while minimizing adverse effects. Targeting GLUT3 or the O-GlcNAcylation pathway could precisely manipulate Treg activity within tumors, leading to better outcomes in cancer patients.

Link: https://www.postech.ac.kr/eng/postech-team-pioneers-new-cancer-therapy-strategy-targeting-glut3-in-regulatory-t-cells-to-supercharge-anti-tumor-immunity/

Cells have evolved a variety of ways to compensate for stress-inducing circumstance, such as heat, cold, low nutrient availability, mutational damage caused by toxins, and so forth. Perhaps the most studied of these mechanisms is autophagy, which recycles damaged cell components into raw materials. A cell structure is flagged, then engulfed by a membrane called an autophagosome, which is then transported to a lysosome, where it deposits its contents to be broken down by enzymes. It is clear from many lines of research that increased autophagy slows the progression of aging, most likely by removing more of the molecular damage that contributes to dysfunction.

Autophagy is far from the only stress resistance mechanism that operates in cells. Others focused on recycling of damaged proteins such as the ubiquitin-proteasome system and unfolded protein response are also influential on the pace of aging. So in humans, can one trace variants in gene sequence and gene expression to correlate performance of these stress resistance systems with longevity? That is the topic of today's open access paper, in which the researchers compare associations with stress resistance system performance and longevity in human data.

Biology of Healthy Aging: Biological Hallmarks of Stress Resistance Related and Unrelated to Longevity in Humans

Stress resistance is highly associated with longer and healthier lifespans in various model organisms, including nematodes, fruit flies, and mice. However, we lack a complete understanding of stress resistance in humans; therefore, we investigated how stress resistance and longevity are interlinked in humans. Using more than 180 databases, we identified 541 human genes associated with stress resistance. The curated gene set is highly enriched with genes involved in the cellular response to stress. The Reactome analysis identified 398 biological pathways, narrowed down to 172 pathways using a medium threshold. We further summarized these pathways into 14 pathway categories, e.g., cellular response to stimuli/stress, DNA repair, gene expression, and immune system.

There were overlapping categories between stress resistance and longevity, including gene expression, signal transduction, immune system, and cellular responses to stimuli/stress. The categories include the PIP3-AKT-FOXO and mTOR pathways, known to specify lifespans in the model systems. They also include the accelerated aging syndrome genes (WRN and HGPS/LMNA), while the genes were also involved in non-overlapped categories. Notably, nuclear pore proteins are enriched among the stress-resistance pathways and overlap with diverse metabolic pathways.

This study fills the knowledge gap in humans, suggesting that stress resistance is closely linked to longevity pathways but not entirely identical. While most longevity categories intersect with stress-resistance categories, some do not, particularly those related to cell proliferation and beta-cell development. We also note inconsistencies in pathway terminologies with aging hallmarks reported previously, and propose them to be more unified and integral.

Alzheimer's disease progresses through stages. The well known, slow accumulation of misfolded amyloid-β over years is only the early foundation of the condition, in and of itself producing little more than mild cognitive impairment. Amyloid-β, however, enables the onset of a state of chronic inflammation and tau protein aggregation that feeds upon itself and grows in severity, disrupting function and killing brain cells until it ultimately kills the patient. Researchers here find a potential target to slow or prevent the aggregation of altered tau protein in mouse models. Since these models are highly artificial, as aged mice do not normally suffer anything resembling a tauopathy, further work will be needed to demonstrate relevance to the natural human condition of Alzheimer's disease.

Over two dozen different diseases have been identified so far whose hallmark neuropathological feature is the presence of neuronal and/or glial accumulations of tau protein. Tau is a predominantly neuronal protein that binds to tubulin to promote assembly of the microtubule network that underpins intracellular transport. Its function is regulated by numerous post-translational modifications, such as phosphorylation, ubiquitination, and acetylation. In pathological states, tau protein undergoes aberrant modifications - predominantly hyperphosphorylation - then dissociates from microtubules, misfolds, propagates to neighboring cells and accumulates into intracellular neurofibrillary tangles (NFTs).

Alzheimer's disease is one of at least 26 diseases characterized by tau-positive accumulation in neurons, glia or both. However, it is still unclear what modifications cause soluble tau to transform into insoluble aggregates. We previously performed genetic screens that identified tyrosine kinase 2 (TYK2) as a candidate regulator of tau levels. Here we verified this finding and found that TYK2 phosphorylates tau at tyrosine 29 (Tyr29) leading to its stabilization and promoting its aggregation in human cells. We discovered that TYK2-mediated Tyr29 phosphorylation interferes with autophagic clearance of tau. We also show that TYK2-mediated phosphorylation of Tyr29 facilitates pathological tau accumulation in P301S tau-transgenic mice. Furthermore, knockdown of Tyk2 reduced total tau and pathogenic tau levels and rescued gliosis in a tauopathy mouse model. Collectively, these data suggest that partial inhibition of TYK2 could thus be a strategy to reduce tau levels and toxicity.

Link: https://doi.org/10.1038/s41593-024-01777-2

Hunter-gatherer populations in which fairly high levels of exercise are the norm have excellent heart health in later life in comparison to more sedentary first world populations. Hunter-gatherers exhibit very little atrial fibrillation, for example. So it isn't all that surprising to see that greater levels of exercise in those first world populations correlate with reduced incidence of atrial fibrillation, one more item in the long list of reasons to undertake more rather than less physical activity.

Researchers focused on atrial fibrillation, a condition in which the heart's upper two chambers beat rapidly and irregularly instead of at a consistent pace. If left untreated, this can lead to stroke, heart failure, and other issues. While past studies have linked exercise to reduced risk of this type of arrhythmia, nearly all of these analyses have relied on participants' often inaccurate estimates of their own activity levels. The current study used data recorded from the fitness tracker Fitbit to objectively measure physical activity in more than 6,000 men and women across the United States. The results showed that those with higher amounts of weekly physical activity were less likely to develop atrial fibrillation. Notably, even modest amounts of moderate to vigorous exercise, which can range from taking a brisk walk or cleaning the house to swimming laps or jogging, were associated with reduced risk.

Specifically, study participants who averaged between 2.5 and 5 hours per week, the minimum amount recommended by the American Heart Association, showed a 60 percent lower risk of developing atrial fibrillation. Those who averaged greater than 5 hours had a slightly greater (65 percent) reduction. In the sole earlier study that used activity monitors to investigate atrial fibrillation, researchers provided Fitbit-style monitors to the participants and tracked them for only a week, an approach that may not have accurately captured their normal workout habits. The new investigation assessed participants for a full year and included only those who already owned the devices.

Link: https://nyulangone.org/news/though-more-better-even-moderate-amounts-exercise-may-reduce-risk-common-heart-condition

Harmful changes in the behavior of the innate immune cells known as macrophages, and their analogous counterparts in the brain, called microglia, show up everywhere in investigations of aging and age-related disease. Macrophages are resident in all tissues, and participate in normal tissue maintenance and function in addition to chasing down pathogens and eliminating errant cells. Which activities are undertaken by a given macrophage are determined by its state; a crude division can be made between M1 macrophages that are pro-inflammatory and aggressive versus M2 macrophages that are anti-inflammatory and engage in tissue maintenance. Circumstances such as the level of damage in the tissue environment and level of inflammatory signaling will bias macrophages into one camp or the other.

The presence of too many inflammatory M1 macrophages may be an important feature of aging, a maladaptive reaction to rising levels of damage and inflammatory signaling - that signaling then further amplified by the macrophages themselves. But beyond this, there is also the question of cellular senescence. Cells become senescent in response to replication stress and mutational damage, as well as in response to tissue injury. These cells pump out inflammatory signaling but are efficiently removed by the immune system in youth. The immune system becomes less capable with age, and thus senescent cells accumulate. Many of these are macrophages. At some point all of this inflammation tips over into tissue dysfunction.

Today's open access paper is an example of the consequences of too many inflammatory and senescent macrophages. The researchers trace a path from the reduced estrogen production of menopause to excessive inflammatory and senescent macrophages in bone tissue, leading to disruption of the usual maintenance of bone. That in turn leads to an accelerated loss of bone density, manifesting as osteoporosis. Regular clearance of these errant macrophages, or some form of reprogramming to alter their state, may help to sever the link between menopause and osteoporosis, and slow the age-related decline of bone density.

Dynamic transcriptome analysis of osteal macrophages identifies distinct subset with senescence features in experimental osteoporosis

Given the potential fundamental function of osteal macrophages in bone pathophysiology, we study here their precise function in experimental osteoporosis. Gene profiling of osteal macrophages from ovariectomized mice demonstrated the upregulation of genes that were involved in oxidative stress, cell senescence, and apoptotic process. Single cell RNA sequencing analysis revealed that osteal macrophages were heterogenously clustered into 6 subsets that expressed proliferative, inflammatory, anti-inflammatory, and efferocytosis gene signatures.

Importantly, postmenopausal mice exhibited a 20-fold increase in the subset that showed a typical gene signature of cell senescence and inflammation. These findings suggest that the decreased production of estrogen due to postmenopause altered the osteal macrophages subsets, resulting in a shift toward cell senescence and inflammatory conditions in the bone microenvironment.

Furthermore, adoptive macrophage transfer onto calvarial bone was performed and mice that received oxidative-stressed macrophages exhibited greater osteolytic lesions than control macrophages, suggesting the role of these cells in development of inflammaging in bone microenvironment. Consistently, depletion of senescent cells and oxidative-stressed macrophages subset alleviated the excessive bone loss in postmenopausal mice. In conclusion, our data provided a new insight into the pathogenesis of osteoporosis and sheds light on a new therapeutic approach for the treatment/prevention of postmenopausal osteoporosis.

Some forms of therapy can be delivered to the brain by being sprayed into the nasal cavity; viral vectors, for examples, and extracellular vesicles in the example here. Extracellular vesicles carry much of the signaling that passes between cells, and can be harvested from cell culture populations of stem cells. The benefits of first generation stem cell therapies are thought to result from the signaling produced by the transplanted cells in the short time before they die, and thus the field is shifting towards the use of stem cell derived vesicles instead. Researchers here show that stem cell derived extracellular vesicles delivered via nasal spray can beneficially dampen inflammation in microglia, innate immune cells of the brain. Overly inflammatory microglia are implicated in the development of neurodegenerative conditions such as Alzheimer's disease.

As current treatments for Alzheimer's disease (AD) lack disease-modifying interventions, novel therapies capable of restraining AD progression and maintaining better brain function have great significance. Anti-inflammatory extracellular vesicles (EVs) derived from human induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs) hold promise as a disease-modifying biologic for AD. This study directly addressed this issue by examining the effects of intranasal (IN) administrations of hiPSC-NSC-EVs in 3-month-old 5xFAD mice.

IN administered hiPSC-NSC-EVs incorporated into microglia, including plaque-associated microglia, and encountered astrocytes in the brain. Single-cell RNA sequencing revealed transcriptomic changes indicative of diminished activation of microglia and astrocytes. Multiple genes linked to disease-associated microglia, NLRP3-inflammasome, and IFN-1 signalling displayed reduced expression in microglia. Astrocytes also displayed reduced expression of genes linked to IFN-1 and interleukin-6 signalling. Furthermore, the modulatory effects of hiPSC-NSC-EVs on microglia in the hippocampus persisted 2 months post-EV treatment without impacting their phagocytosis function. The extent of astrocyte hypertrophy, amyloid-beta plaques, and p-tau were also reduced in the hippocampus. Such modulatory effects of hiPSC-NSC-EVs also led to better cognitive and mood function.

Thus, early hiPSC-NSC-EV intervention in AD can maintain better brain function by reducing adverse neuroinflammatory signalling cascades, amyloid-beta plaque load, and p-tau. These results reflect the first demonstration of the efficacy of hiPSC-NSC-EVs to restrain neuroinflammatory signalling cascades in an AD model by inducing transcriptomic changes in activated microglia and reactive astrocytes.

Link: https://doi.org/10.1002/jev2.12519

There is some evidence for the gut microbiome to play an important role in a range of comparatively poorly understood conditions involving pain, inflammation, and at least the suspicion of autoimmunity, from the better researched rheumatoid arthritis to the dark forest of overlapping symptoms containing fibromyalgia, myofascial pain syndrome, idiopathic peripheral neuropathies, and more. If many of these conditions do derive from microbial activities, however indirectly, this may go some way towards explaining the lack of progress towards finding definitive mechanisms and causes - until comparatively recently, no-one was looking at the gut microbiome.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder. The hallmark of RA is progressive joint disease, with potential for systemic involvement. Understanding the RA disease spectrum with recognition of at risk individuals has propelled RA research into prevention strategies. The generation of IgA class anticitrullinated protein antibodies (ACPAs) in individuals at risk of RA, combined with epidemiological links with smoking and periodontal disease, points to a mucosal origin of inflammation. The mucosal origin hypothesis proposes that localised inflammation at mucosal sites can initiate a broader immune response, via T cell activation and a subsequent inflammatory cytokine cascade, leading to B cell antibody production. Supporting this, an immunoglobulin class switch from IgA ACPAs to IgG ACPAs indicates potential triggering of systemic autoimmunity by diverse antigenic stimuli at mucosal sites. This shift, accompanied with broadening of antibody targets, suggests that mucosal barrier deterioration and the ensuing spread of an IgG ACPA response might be more significant in the initial stages of RA than the loss of tolerance to self-antigens.

Profiling of the gut microbiome in individuals at risk of RA and people diagnosed with RA consistently demonstrates a dysbiotic microbiome when compared with healthy controls. However, there remains little consensus on the bacterial constituent members of an RA-related dysbiosis. Subsequently, a variety of gut bacteria have been implicated as a potential impetus in the development of RA, none more so than Prevotella copri. Prevotella species have been demonstrated to be overabundant in new-onset rheumatoid arthritis (NORA), in at risk individuals and especially those with genetic risk. Their abundance decreases after disease-modifying antirheumatic drug (DMARD) therapy, with reversion to a eubiotic state on treatment. Furthermore, mouse models support a role for Prevotellaceae strains derived from patients with RA in RA development. However, Prevotellaceae overabundance does not appear to be an ubiquitous finding across all RA gut microbiome studies.

This work aimed to resolve the conflicting reports on Prevotellaceae abundance in the development of rheumatoid arthritis (RA) and to observe structural, functional and temporal changes in the gut microbiome in RA progressors versus non-progressors. Our data suggest conflicting reports on Prevotellaceae overabundance are likely due to sampling within a heterogeneous population along a dynamic disease spectrum, with certain Prevotellaceae strains/clades possibly contributing to the establishment and/or progression of RA. Gut microbiome changes in RA may appear at the transition to clinical arthritis as a late manifestation, and it remains unclear whether they represent a primary or secondary phenomenon.

Link: https://doi.org/10.1136/ard-2024-226362

Most proteins in the body are continually replaced on a fairly short time frame, either because replacement takes place inside cells, or because the cells themselves are replaced over time. In the few lasting cell populations, such as neurons in the brain and oocytes in the ovaries, there is the potential for cells and even individual protein molecules in those cells to have a life span that is as long as the overall life span of the animal or person. This is a point of concern because large molecules in the cell can become chemically altered in harmful ways over time, negatively affecting cell function. At the present time, it is far from clear as to how best to approach this problem, and how much of a contribution to age-related loss of function it provides.

In today's open access paper, researchers characterize long-lived proteins in oocytes and the surrounding ovary structures. This characterization doesn't demonstrate that the presence of long-lived proteins, and thus loss of function due to damaging chemical alterations, is a major contributing cause of dysfunction. But is is strongly suggestive that there will be some contribution to loss of function. Unlike the brain, another location of long-lived proteins, the ovaries age into loss of function comparatively early in life. Are long-lived proteins meaningful in this early aging, or is it other factors? That question remains to be answered.

Exceptional longevity of mammalian ovarian and oocyte macromolecules throughout the reproductive lifespan

The female reproductive system is the first to age in the human body with fertility decreasing for women in their mid-thirties and reproductive function ceasing completely at menopause. In the ovary, aging is associated with a loss in gamete quantity and quality which contributes to infertility, miscarriages, and birth defects. Moreover, the age-dependent loss of the ovarian hormone, estrogen, has adverse general health outcomes. These sequelae are significant as women globally are delaying childbearing and the gap between menopause and lifespan is widening due to medical interventions.

Although aging is a multifaceted process, loss of proteostasis and dysfunctional protein quality control pathways are hallmarks of reproductive aging. The mammalian ovary is comprised of a fixed and nonrenewable pool of long-lived cells or oocytes. In humans, oocytes initiate meiosis during fetal development, and by birth, all oocytes are arrested in the cell cycle. This cell cycle arrest is maintained until ovulation, which occurs any time between puberty and menopause, and thus can span decades. The oocytes are particularly sensitive to protein metabolism alterations because they contribute the bulk cytoplasm to the embryo following fertilization. Thus, maternal proteins produced during oogenesis are essential to generate high-quality gametes.

The ovarian microenvironment is a critical determinant of gamete quality and has been shown to become fibro-inflamed and stiff with age. Although a small number of oocyte-specific proteins have been identified as long-lived, including cohesins and several centromere-specific histones, there has not been a discovery-based approach to define the long-lived proteome of the ovary and oocyte. Thus, the potential contribution of long-lived proteins (LLPs) to the age-related deterioration of the reproductive system in mammals remains to be elucidated. In this study we used multi-generational whole animal metabolic stable isotope labeling and leading mass spectrometry (MS)-based quantitative proteomic approaches to visualize and identify ovarian and oocyte long-lived macromolecules in vivo during milestones relevant to the reproductive system.

LLPs tend to be part of large protein complexes and include histones, nuclear pore complex proteins, lamins, myelin proteins, and mitochondrial proteins. In the ovary, the major categories of LLPs included histones, cytoskeletal proteins, and mitochondrial proteins. Our findings provide a novel framework for how long-lived structures may regulate gamete quality. Long-lived macromolecules localized throughout the ovary including the follicular compartment with prominent signals in the granulosa cells of primordial and primary follicles relative to later stage growing follicles. These findings are consistent with the knowledge that the squamous pre-granulosa cells surrounding the oocyte within primordial follicles form early in development. These squamous granulosa cells are generally thought to lack the ability to undergo mitotic division until follicles are activated to grow, so it is not surprising that we observed long-lived macromolecules persisting within them. Thus, it is possible that these long-lived molecules will accumulate more damage in primordial follicles that remain quiescent for longer periods relative to those that activate earlier. Whether such damage occurs and how it translates into decreased follicle survival or gamete quality will require further investigation.

Within the extrafollicular ovarian environment, the ovarian surface epithelium (OSE) exhibited a striking enrichment of long-lived molecules. The OSE is highly dynamic due to repeated post-ovulation wound healing and repair, and its regenerative capacity occurs through a somatic stem/progenitor cell-mediated process. Interestingly, LLPs are retained in other cells undergoing repeated asymmetric divisions and are speculated to contribute to the reproductive aging process. Consistent with this possibility, the architecture and wound healing ability of the OSE is altered with advanced reproductive age.

With old age, everyone develops atherosclerosis, a condition characterized by the formation and growth of fatty plaques that narrow and weaken blood vessels. The more cholesterol present in an atherosclerotic plaque, the softer the plaque structure, and the greater the likelihood of fragmentation and rupture leading to a heart attack or stroke. Local excesses of cholesterol cause cell dysfunction, and in plaque this is particularly important in the macrophages that arrive to attempt to return excess cholesterol to the blood stream and otherwise repair the local damage. Instead of conducting repair, the cells instead become dysfunction and inflammatory. Many become senescent cells, and there is compelling evidence for the presence of senescent cells to make the dysfunction in plaque worse.

Recently, cellular senescence-induced unstable carotid plaques have gained increasing attention. In this study, we utilized bioinformatics and machine learning methods to investigate the correlation between cellular senescence and the pathological mechanisms of unstable carotid plaques. Our aim was to elucidate the causes of unstable carotid plaque progression and identify new therapeutic strategies. First, differential expression analysis was performed on a test set to identify differentially expressed genes (DEGs) between the unstable plaque group and the control group. These DEGs were intersected with cellular senescence-associated genes to obtain 40 cellular senescence-associated (CSA)-DEGs.

First, we investigated the expression and function of CSA-DEGs in unstable carotid plaques. The expression of CSA-DEGs in cells from unstable carotid plaques differed significantly from the control group. These genes are mainly related to cellular senescence, apoptosis, cell proliferation regulation, and inflammatory response. Typically, the characteristics of cellular senescence are described as irreversible proliferation arrest and senescence-associated secretory phenotype (SASP). Additionally, these genes are involved in pathways such as the MAPK signaling pathway, PI3K-Akt signaling pathway, FoxO signaling pathway, and HIF-1 signaling pathway. These pathways play crucial roles in the aging process, and their dysregulation is closely associated with the progression of unstable carotid plaques. Interestingly, we also observed that CSA-DEGs are closely related to T lymphocyte proliferation and cellular immunity, which is consistent with previous studies.

Link: https://doi.org/10.1038/s41598-024-78251-3

We live in a world in which near all species exhibit degenerative aging, yet some few species exhibit negligible aging until very late life, and a very much smaller number of species appear not to age at all. Aging isn't inevitable, yet it is near universal. Why has evolution produced this outcome? While there is a consensus answer to this question centered around the concept of antagonistic pleiotropy, the evolution of aging is a field of research characterized by continual debate, an ever changing sea of novel ideas that come and go from year to year. In part this is because it is challenging to prove any given theory definitively right or definitively wrong, but also in part because we live in an age of biotechnology, in the midst of a flood of new data on the biochemistry of aging, any piece of which might be argued to change the bigger picture in some way.

Ageing is generally regarded as a non-adaptive by-product of evolution. Based on this premise three classic evolutionary theories of ageing have been proposed. These theories have dominated the literature for several decades. Despite their individual nuances, the common thread which unites them is that they posit that ageing results from a decline in the intensity of natural selection with chronological age. Empirical evidence has been identified which supports each theory. However, a consensus remains to be fully established as to which theory best accounts for the evolution of ageing.

A consequence of this uncertainty are counter arguments which advocate for alternative theoretical frameworks, such as those which propose an adaptive origin for ageing, senescence, or death. Given this backdrop, this review has several aims. Firstly, to briefly discuss the classic evolutionary theories. Secondly, to evaluate how evolutionary forces beyond a monotonic decrease in natural selection can affect the evolution of ageing. Thirdly, to examine alternatives to the classic theories. Finally, to introduce a pluralistic interpretation of the evolution of ageing. The basis of this pluralistic theoretical framework is the recognition that certain evolutionary ideas will be more appropriate depending on the organism, its ecological context, and its life history.

Link: https://doi.org/10.1007/s10522-024-10143-5